Angiogenesis is a process through which new capillaries form from pre-existing microvessels. Angiogenesis may normally occur in the cases of embryonic development, tissue regeneration, wound healing, and development of corpus luteum in terms of changes in the periodic reproductive system of the female. In the cases described above, angiogenesis is strictly controlled to proceed.
Vascular endothelial cells for adults grow very slowly and do not divide relatively well compared to other types of cells. A process of angiogenesis generally consists of remodeling of blood vessels and generating of new capillaries through degradation of vascular basement membrane upon a protease that is stimulated by a stimulating factor, and tubular formation through movement, proliferation, and differentiation of vascular endothelial cells.
However, there are diseases caused when angiogenesis is not autonomously controlled, but becomes pathological. Diseases associated with angiogenesis in pathological conditions include hemangioma, angiofibroma, vascular malformation, and cardiovascular diseases, such as atherosclerosis, vascular adhesion, and scleroderma. Ophthalmologic diseases associated with angiogenesis include macular degeneration, corneal graft angiogenesis, neovascular glaucoma, diabetic retinopathy, corneal diseases associated with angiogenesis, macular degeneration, pterygium, retinal degeneration, retrolental fibroplasia, and trachoma. chronic inflammatoary diseases, such as arthritis, psoriasis, skin disease, such as capillarectasia, granuloma pyogenicum, seborrheic dermatitis, and acne, Alzheimer's disease, and obesity are also related to angiogenesis, and the growth of cancer and metastasis are definitely dependent upon angiogenesis (refer to D'Amato R J et al., Ophthalmology, 102(9), pp 1261-1262, 1995; Arbiser J L, J. Am. Acad. Dermatol., 34(3), pp 486-497, 1996; O'Brien K D et al. Circulation, 93(4), pp 672-682, 1996; Hanahan D et al., Cell, 86, pp 353-364, 1996).
Arthritis, which is a representative inflammatory disease, is caused by autoimmune abnormalities, but due to pathological progression, chronic inflammation in a synovial cavity between joints may induce angiogenesis, thereby destroying cartilage. That is, by means of cytokines inducing inflammation, synovial and vascular endothelial cells are proliferated in the synovial cavity, leading to angiogenesis, and accordingly, the pannus junction, which is the connective tissue layer formed in the cartilage, thereby destroying the cartilage acting as a cushion (refer to Koch A E et al., Arthritis. Rheum., 29, pp 471-479, 1986; Stupack D G et al., Braz J. Med. Biol. Rcs., 32(5), pp 578-581, 1999; Koch A E, Atrhritis. Rheum., 41(6), pp 951-962, 1998).
Many ophthalmologic diseases including blindness occurring in millions of worldwide people year after year are caused by angiogenesis (refer to Jeffrey M I et al., J. Clin. Invest., 103, pp 1231-1236, 1999). Representative examples of diseases that are caused by angiogenesis include macular degeneration in the old, diabetic retinopathy, retinopathy of prematurity, neovascular glaucoma, and corneal diseases associated with angiogenesis (Adamis A P et al., Angiogenesis, 3, pp 9-14, 1999). In particular, diabetic retinopathy is a complication of diabetes, eventually being blinded due to invasion of the capillaries in the retina into the vitreous cavity.
Psoriasis characterized by redness and scaling skin is also a chronic proliferative disease occurring on the skin, but if not cured, psoriasis is accompanied by pain and deformity. Keratinocytes normally proliferate once a month, whereas keratinocytes in patients with psoriasis proliferate at least once a week. Since such rapid proliferation requires the supply of much blood, angiogenesis is actively bound to happen (Folkman J, J. Invest. Dermatol., 59, pp 40-48, 1972).
In particular, in the case of cancer, angiogenesis plays an important role in the growth and metastasis of cancer cells. Tumors receive the supply of nutrients and oxygen necessary for the growth and proliferation through angiogenesis. In addition, new blood vessels infiltrated into tumors provide an opportunity for metastatic cancer cells to enter into the blood circulatory system, resulting in metastasis of the cancer cells (Folkman and Tyler, Cancer Invasion and metastasis, Biologic mechanisms and Therapy (S. B. Day ed.) Raven press, New York, pp 94-103, 1977; Polverini P J, Crit. Rev. Oral. Biol. Med., 6(3), pp 230-247, 1995). The main cause of death in cancer patients is metastasis, and metastasis is the reason why chemotherapy and immunotherapy that are currently used in clinical trials fail to contribute to increasing the survival rates of cancer patients.
When looking at a metastasis process of most solid cancers, the process is carried out as follows: proliferation of cancer cells has been made in the first occurrence place of the cancer cells, and once a lump of the cancer cells gets larger, the cancer cells that are apart from the lump of the cancer cells to move to another location are moved through blood vessels and settled in a secondary place to allow the cell proliferation again. In the process, to move the cancer cells to another location through the blood vessels, the invasion of the cancer cells must occur. Here, to decompose extracellular matrix components, proteases are overexpressed by the cancer cells, and examples of the proteases include matrix metalloproteinases (MMPs), cathepsins, and various proteinases.
Cathepsin is a lysosome enzyme that breaks down proteins at a low pH, and may be classified into a serine protease (e.g., cathepsins A and G), an aspartyl protease (e.g., cathepsins D and E), and a cysterin protease (e.g., cathepsins B, C, F, H, K, L1, V, O, S, W, and Z). Cathepsin is involved in each specific physiological processes, and that is, cathepsin may be involved in antigen presentation in the immune system, collagen turnover between bonds and cartilages, and processing of neuropeptides and hormones. A lack of cathepsins causes various symptoms of diseases, and overexpression of cathepsin also causes a variety of diseases. In particular, it is known that overexpression of cysterin cathepsin (cathepsins B, F, H, K, L, V, S, and Z) is involved in cancer and metastasis (Reiser J et al., J Clin Invest. 120(10), 3421-31, 2010).
Cathepsin in most cases has a role as a ribosome protease in controlling a physiological function within a cell. As a protein that is secreted outside a cell and performs a proteolytic function, cathepsin S is disclosed. Cathepsin S in a cellular ribosome is involved in antibody processing or apoptosis, whereas cathepsin S secreted outside a cell breaks down extracellular matrix components, such as laminin, fibronectin, elastin, or collagen. It is deemed that, according to the functions above, cathepsin S is involved in the process of invasion of cancer cells and angiogenesis.
In a recent report, it is confirmed that expression of cathepsin S is significantly increased in a colorectal cancer tissue of a patient having colorectal cancer as compared with expression of cathepsin S in a normal colorectal tissue (refer to Gormley J A et al., Br J Cancer, 105(10), 1487-94, 2011). Furthermore, it has been reported that, when expression of cathepsin S is decreased by introducing siRNA, which targets a cathepsin S gene, to a liver cancer cell, a decrease in proliferation of the liver cancer cell, invasion of cancer, angiogenesis has been resulted (Fan Q et al., Biochem Biophys Res Commun, 425(4), 703-10, 2012).
In the case of breast cancer, prognosis of a patient having breast cancer metasized to lymphatic nodes is significantly related to cathepsin D staining in a breast cancer tissue cathepsin D, whereas cathepsin D is not related to a patient having non-metastatic lymphatic nodes (Henry J A et al., Cancer, 65(2), 265-71, 1990). On the basis of these results, it was suggested that cathepsin D played an important role in metastasis of breast cancer and invasion of cancer, but according to other studies on the same subject, it was resulted that, when breast cancer cell lines, such as MCF7, MDA-MB-231, and MDA-MB-435, were used to carry out experimental metastasis, cathepsin D had no relevance to invasion of breast cancer cells (Johnson M D et al., Cancer Res., 53(4), 873-7, 1993). As in the case of liver cancer, it is expected that cathepsin S may have important effects on metastatic breast cancer cells.
Also, inflammatory bowel disease (IBDs) is classified into two different diseases, i.e., ulcerative colitis and Crohn's disease, that is clinically similar with each other but are different from each other in terms of histological findings and endoscopic and immunological aspects. Such an IBD is known as a disease in which activation of inflammatory cells is important.
Sustained or inappropriate activation of the intestinal immune system plays an important role in pathological physiology of chronic mucosal inflammation, and more particularly, due to invasion of neutrophilic leukocytes, macrophages, lymphocytes, and mastocytes, mucosal destruction and ulcer are eventually caused. Neutrophilic leukocytes that are invaded and activated are considered as an important cause of active oxygen/nitrogen species, and such active species can induce a cellular oxidative stress upon a cytotoxic agent, such as cross-linked proteins, lipids, and nucleic acids, thereby causing epithelial dysfunction and damages.
When having inflammatory diseases, various inflammatory cytokines are secreted from the mucous membrane of the intestinal canal. TNF-α appears at a high level at a lumen of the large intestine and in intestinal epithelial cells of a patient having ulcerative colitis. According to recent studies, TNF-α is known to play an important role as a cause of ulcerative colitis. Infliximab, which is an anti-TNF-α antibody, is known to be effective in the treatment of not only boils, but also Crohn's disease that was not treated before. However, such treatment is expensive, and may cause side effects, such as transfusion reactions or infectious complications, in some patients.
Monocyte chemoattractant protein-1 (MCP-1) is a member of the C—C chemokine family having a molecular mass of 14 kDa, and mobilizes and activates mainly monocytes/macrophages in inflamed areas. MCP-1 is localized on epithelial cells of the large intestine, and it has been reported that the expression of MCP-1 is related to the invasion of monocytes in the mucous membrane of a patient having IBDs. Unlike other types of chemokines, MCP-1 binds to CCR2 only, and thus the binding of MCP-1/CCR2, as a main regulator of the mobilization of monocytes, is known to play an important role in IBDs.
In addition, interleukin 8 (IL-8) is known to be significantly increased in the mucous membrane of a patient having IBDs, thereby promoting capillary neovascularization. The more severe inflammation the large intestine has, the more the IL-8 is expressed. In addition, in an animal model using rodents, it is known that an antibody specific to the IL-8 reduces intestinal inflammation. Here, changes in intracellular Ca2+ are regarded as important factors in the reduction of the IL-8.
As a therapeutic agent currently available for IBDs, 5-aminosalicylic acid (5-ASA)-based drugs that inhibit production of prostaglandins are used, and examples thereof are sulfasalazine and a steroidal immunosuppressant drug.
Sulfasalazine may cause side effects, such as fullness, headache, rash, liver diseases, leucopenia, agranulocytosis, or male infertility, or adverse effects. In addition, it is unclear whether sulfasalazine has sufficient inhibitory effects on the recurrence in patients having an incision on the affected part of the intestines to patients showing improvement.
A steroid immunosuppressant is an andrenocortical steroid and has acknowledged short-term effects. However, its long-term prognosis cannot be improved, and due to side effects including induced infectious disease, secondary adrenocortical insufficiency, peptic ulcers, diabetes, mental disorder, and steroidal kidney disease, there is a limitation that the steroid immunosuppressant drug should be used only in an acute situation.
Meanwhile, an angiogenesis inhibitor can be applied as a medicament for the treatment of such various diseases associated with angiogenesis or IBDs, or as an anti-cancer agent for preventing the growth of cancer and metastasis. Thus, recently, studies to treat the diseases described above by inhibiting angiogenesis are actively carried out.